DNA double-strand break (DSB) repair prevents persistent DNA damage, counteracts genome instability and suppresses tumor development. However, DSB repair also has the potential to produce oncogenic chromosome translocations and rearrangements. This highly integrated program will elucidate the mechanism and regulation of DSB repair initiation and its impact on DSB repair choice, chromosome translocation and cancer development in model of lymphoma and breast cancer. In particular, the program will investigate the regulation of microhomology-mediated end-joining (MMEJ), a pathogenic form of DSB repair responsible for a significant fraction of tumorigenic chromosome translocations. Preliminary studies from all projects focusing on DNA processing and CtIP have generated a focused and cohesive program. Dr. Symington will use genetic analysis to assess how DNA resection affects MMEJ and to investigate the competition between MMEJ and other modes of DSB repair. Dr. Symington will also develop sensitive physical resection assays in mammalian cells, a technology which is notably lacking at present. Drs. Gautier and Gottesman will study the mechanism(s) that generate persistent, short ssDNA overhangs at DSBs, an intermediate involved in MMEJ. Their studies will focus on the role of CtIP, a protein involved in initiation of DNA resection. In the third project, Drs. Zha and Dalla-Favera will evaluate the role of CtIP in repair of programmed DSBs during lymphocyte development and malignancy. They will also test the hypothesis that CtIP mediates, at least in part, the oncogenic function of c-Myc including its undefined role in genomic instability. Dr. Baer, will determine how CtIP facilitates breast tumor development in p53-deficient mice and will test whether CtIP loss can also suppress basal-like breast cancer in BRCA1-deficient mice. Finally, he will evaluate the potential role of CtIP in Myc-driven breast tumor development. To accomplish these goals, the projects will rely extensively on three interlinked cores: administrative, molecular analysis of genomic instability and pathology. The project and core leaders have a very strong history of collaboration, joint efforts in training and common interests in genome stability and the mechanisms of its loss in cancer.